Migraine is a common, complex, multifactorial phenotype with a significant genetic contribution that is likely to be polygenic in origin. The complexity of the interaction between environment and genetics has made determination of the inheritance pattern and penetrance difficult. We hypothesize that the predisposition to migraine in an isolated population such as Finland is influenced by a subset of alleles that are enriched in this population, and that may also contribute to migraine in the larger population of migraineurs. Thus we have collected a large, clinically well-characterized sample of Finnish families (652 families, 4062 DNA samples) to ensure a sufficient sample size for subsequent studies. In order to initially identify the high impact susceptibility loci for common forms of migraine we employed a genome wide scan strategy using Finnish multiplex families with exceptional genetic load during the previous funding period (2000-2004). We detected linkage to chromosome 4 in Finnish migraine families, about 30% of families contributing to the linkage signal. Thus we hypothesize that by further restricting the locus and analyzing genes in this region in the disease alleles of the families we can identify specific allelic variants associated with migraine. The restriction and subsequent identification of allelic variants predisposing for complex traits is a major undertaking. Thus a number of mapping and statistical techniques are needed to maximize the chance of success in the project. [unreadable] [unreadable] The aims for the proposed continuation are (1) to further restrict the Chromosome 4 locus using Finnish families, (2) combine genome scans and fine mapping results from migraine mapping studies using other populations, and in addition to dichotomized traits utilize quantitative trait parameters, 3) after restricting the locus, sequence candidate genes/gene areas to identify allelic variations, the general significance of which will be tested in (4) large non-ascertained population cohorts of European twins. [unreadable] [unreadable]